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Gene therapy in animal models of autosomal dominant retinitis pigmentosa.

Rossmiller B, Mao H, Lewin AS - Mol. Vis. (2012)

Bottom Line: Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation.Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression.We conclude that combinatorial approaches have the greatest promise for success.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32611, USA.

ABSTRACT
Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success.

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Human rhodopsin illustrating sites of known mutations or deletions. This figure is based on an illustration at RetNet.
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f1: Human rhodopsin illustrating sites of known mutations or deletions. This figure is based on an illustration at RetNet.

Mentions: Despite the range of genes responsible for ADRP, approximately 30% of ADRP arises from mutations in the rhodopsin gene [19], and therefore, we focus our attention on treatment of mutations affecting the rhodopsin gene (RHO in humans and Rho in mice). Numerous alterations in RHO cause ADRP (Figure 1; RetNet). These mutations do not localize to any specific regions of the protein, suggesting that functional and stable rhodopsin tolerates few amino acid changes. In fact, human rhodopsin protein differs at only 13 positions from the rabbit, 17 positions from the cat, and 18 positions from the mouse. The maximum sequence identity is ≥95% among all of these organisms. The consequences of particular mutations have been analyzed in transfected cells and animal models, sometimes with conflicting results [20]. Rods are also highly susceptible to changes in rhodopsin expression and translocation to the outer segment of photoreceptors, as rhodopsin composes greater than 90% of the outer segment protein [1,5,21-23].


Gene therapy in animal models of autosomal dominant retinitis pigmentosa.

Rossmiller B, Mao H, Lewin AS - Mol. Vis. (2012)

Human rhodopsin illustrating sites of known mutations or deletions. This figure is based on an illustration at RetNet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472929&req=5

f1: Human rhodopsin illustrating sites of known mutations or deletions. This figure is based on an illustration at RetNet.
Mentions: Despite the range of genes responsible for ADRP, approximately 30% of ADRP arises from mutations in the rhodopsin gene [19], and therefore, we focus our attention on treatment of mutations affecting the rhodopsin gene (RHO in humans and Rho in mice). Numerous alterations in RHO cause ADRP (Figure 1; RetNet). These mutations do not localize to any specific regions of the protein, suggesting that functional and stable rhodopsin tolerates few amino acid changes. In fact, human rhodopsin protein differs at only 13 positions from the rabbit, 17 positions from the cat, and 18 positions from the mouse. The maximum sequence identity is ≥95% among all of these organisms. The consequences of particular mutations have been analyzed in transfected cells and animal models, sometimes with conflicting results [20]. Rods are also highly susceptible to changes in rhodopsin expression and translocation to the outer segment of photoreceptors, as rhodopsin composes greater than 90% of the outer segment protein [1,5,21-23].

Bottom Line: Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation.Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression.We conclude that combinatorial approaches have the greatest promise for success.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32611, USA.

ABSTRACT
Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success.

Show MeSH
Related in: MedlinePlus